What is the initial treatment approach for a patient with low-grade myelodysplastic syndrome (MDS)?

Initial Treatment Approach for Low-Grade Myelodysplastic Syndrome

For patients with low-grade (lower-risk) MDS, treatment should be directed by the specific symptomatic cytopenia present, with erythropoiesis-stimulating agents (ESAs) as first-line therapy for anemia in patients without del(5q), and lenalidomide for those with del(5q), while all patients require appropriate supportive care. 1

Risk Stratification Framework

Lower-risk MDS encompasses patients in the following categories 1:

• IPSS: Low and Intermediate-1 (INT-1)
• IPSS-R: Very low, low, and some intermediate-risk
• WPSS: Very low, low, and intermediate categories

The primary therapeutic goal for this population is hematologic improvement and quality of life enhancement, rather than altering disease natural history 1

Treatment Algorithm by Cytopenia Type

Symptomatic Anemia (Most Common Presentation)

Patients WITHOUT del(5q) Deletion:

First-Line: ESAs 1

• Recombinant EPO: 30,000-80,000 units weekly, OR
• Darbepoetin alfa: 150-300 mg weekly
• Response rate: 40-60% when baseline EPO <200-500 U/L and transfusion requirement is low/absent 1
• Median response duration: 20-24 months 1
• Time to response: 8-12 weeks 1
• Enhancement strategy: Add G-CSF to improve efficacy 1
• EMA approval: EPO alpha (and biosimilars) for serum EPO <200 U/L 1

Prognostic factors predicting ESA response 1:

• Low baseline serum EPO level (<200-500 U/L)
• Absent or limited transfusion requirement
• IPSS low or intermediate-1
• Marrow blasts <5%
• No multilineage dysplasia

Second-Line Options (after ESA failure): 1

• Luspatercept: For MDS with ring sideroblasts (MDS-RS) or SF3B1 mutation; FDA/EMA approved with 63% erythroid response and 38% transfusion independence in phase II, confirmed in phase III 1
• ATG ± cyclosporine: 25-40% erythroid response in selected patients (younger <65 years, transfusion history <2 years, normal karyotype or trisomy 8, no excess blasts, HLA DR15 genotype, thrombocytopenia, marrow hypocellularity) 1
• Azacitidine: 30-40% achieve RBC transfusion independence (if approved in your region) 1
• Lenalidomide ± EPO: 25-30% RBC transfusion independence in non-del(5q) patients 1

Patients WITH del(5q) Deletion:

First-Line: Lenalidomide 1

• Dosing: 10 mg/day for 3 weeks every 4 weeks 1
• Response rate: 60-65% achieve RBC transfusion independence 1
• Median response duration: 2-2.5 years 1
• Cytogenetic response: 50-75% (including 30-45% complete cytogenetic response) 1
• In EU: Approved only after ESA failure or ineligibility 1

Critical monitoring for lenalidomide 1:

• Grade 3-4 neutropenia and thrombocytopenia occur in ~60% during first weeks
• Close blood count monitoring required with dose reduction/G-CSF addition as needed
• TP53 mutations (present in ~20% of del(5q) MDS) confer resistance and higher AML progression risk—these patients require intensified surveillance and consideration of higher-risk MDS approaches 1

Note: ESAs have lower response rates and shorter duration in del(5q) patients compared to non-del(5q) 1

Symptomatic Neutropenia

Management approach 1:

• Febrile episodes: Broad-spectrum antibiotics immediately 1
• Short-term G-CSF: Can improve neutropenia in 60-75% of cases; add during severe infections 1
• ATG (if favorable features): Can achieve multilineage response including neutrophil improvement 1
• Azacitidine (if approved): May improve neutropenia along with other cytopenias 1

Important caveat: Neutropenia <1,500/mm³ occurs in only 7% of lower-risk MDS and is rarely associated with life-threatening infections unless myelosuppressive drugs are used 1

Symptomatic Thrombocytopenia

Treatment options 1:

• Androgens (high-dose): Improve thrombocytopenia in one-third of patients, but response is generally transient 1
• TPO receptor agonists (romiplostim, eltrombopag): 47-55% platelet response with reduced bleeding events, but NOT approved in Europe and should be restricted to patients with marrow blasts <5% due to concerns about transient blast increases 1
• ATG ± cyclosporine: 35-40% platelet response in selected cases 1
• Azacitidine (if approved): 35-40% platelet response 1

Note: Platelets <50,000/mm³ occur in ~30% of low-risk MDS; prophylactic platelet transfusions are not commonly used outside of myelosuppressive drug therapy 1

Moderate and Asymptomatic Cytopenias

Observation with no active treatment is appropriate 1

Universal Supportive Care Measures

All patients require 1:

• RBC transfusions: Maintain hemoglobin ≥8 g/dL (≥9-10 g/dL with comorbidities or poor functional tolerance); transfuse sufficient units to achieve >10 g/dL to limit chronic anemia effects 1
• Leukocyte-reduced blood products 1
• Irradiated products: For directed-donor units and potential stem cell transplant candidates 1
• CMV-negative products: For CMV-negative recipients when possible 1
• Clinical monitoring and psychosocial support 1
• Quality-of-life assessment: Address physical, functional, emotional, spiritual, and social domains 1

Iron chelation therapy considerations 1:

• Consider starting after ≥70-80 RBC concentrates
• CMR imaging shows heart iron overload (T2* <20 milliseconds) is frequent and associated with decreased left ventricular ejection fraction
• TELESTO trial suggested improved event-free survival with chelation in lower-risk MDS
• Particularly important for patients with good prognosis who may receive prolonged transfusions

Critical Decision Points and Pitfalls

When to escalate to higher-risk MDS treatment approaches 1:

• IPSS-R intermediate-risk patients (decision based on age, comorbidities, severity of cytopenias, somatic mutations, first-line treatment response)
• Resistance to first-line treatment in otherwise lower-risk disease
• Development of TP53 mutations in del(5q) patients on lenalidomide
• Rapid clonal evolution on bone marrow assessment

Common pitfall: Myelosuppression and worsening neutropenia may occur more frequently in the first or second treatment cycles and does not necessarily indicate disease progression 2

ESA survival benefit: Receiving ESAs is an independent favorable prognostic factor for survival with no impact on AML progression 1